Topical formulation

ABSTRACT

Provided herein are topical formulations. The topical formulation may comprise: (i) pregabalin, (ii) water, (iii) DMSO, (iv) a keto acid, and (v) and/or a fatty alcohol. The topical formulation may also comprise (i) pregabalin, (ii) DMSO, (iii) a keto acid and (iv) a fatty acid ester. It has been discovered that the combinations of DMSO with a keto acid such as levulinic acid and/or and a fatty acid ester such as lauryl lactate, or combinations of DMSO with a keto acid such as levulinic acid and/or with a fatty alcohol such as oleyl alcohol are excellent penetration enhancers and, as such, can be incorporated in a skin-applied formulation to facilitate administration of pregabalin.

CROSS-REFERENCE TO RELATED APPLICATIONS

The application is a continuation of U.S. application Ser. No.15/469,963, filed Mar. 27, 2017, which claims the benefit under 35U.S.C. § 119(e) of U.S. Provisional Application 62/390,369, filed Mar.28, 2016, which is hereby incorporated by reference in its entirety.

FIELD

The present disclosure relates to a topical formulation of apharmaceutical agent comprising multiplexed molecular penetrationenhancers.

BACKGROUND

The administration of a drug through the skin for systemic distribution,that is transdermally, can provide compelling advantages relative toother modes of administration. Transdermal administration circumventspotential complications in the gastrointestinal (“GI”) tract, avoidsfirst-pass metabolism in the liver, can allow delivery of an activeingredient with a relatively short biological half-life or a narrowtherapeutic window, facilitates uniform plasma dosing of the activeingredient, and, as above, is broadly preferred from a user complianceperspective.

In spite of the advantages, transdermal administration is limited toonly a small number of drugs. For example, a transdermal patch format iscurrently limited to some thirty drugs (including scopolamine, fentanyl,estradiol, nitroglycerin, nicotine, testosterone, selegiline and methylphenidate). The reason for the paucity of transdermal products to treatserious pain conditions is that the skin presents a formidable barrier.

Structurally, the skin consists of two principle layers: (i) theepidermis, the outermost layer, which varies in thickness from 0.05 mmon the eyelids to 1.5 mm on the palms and soles of the feet but whichtypically averages 80 μm, and (ii) the ‘dermis,’ the inner region,ranges in thickness from 0.4 to 4 mm, with a typical average of 2 mm.The outermost layer of the epidermis (the ‘stratum corneum’) comprisescorneocytes (flattened dead cells which are filled with keratin),interconnected by corneodesmosomes and surrounded by lipids which formlamellar phases. The highly impermeable nature of skin is due primarilyto the stratum corneum. The viable epidermis underlying the stratumcorneum is akin to other living tissue. The dermis provides the skin'sstructural strength as well as the nerve and vascular networks thatsupport the epidermis.

Various factors can affect the skin absorption rates and penetrationdepths of a drug molecule applied in a formulation to the skin,including the nature of the active ingredient, the nature of thevehicle, the pH, and the relative solubility of the active in thevehicle versus the skin. More specifically, drug attributes such assolubility, size and charge, melting point as well as vehicle attributessuch as the drug solubility and dissolution rate, ability to alter themembrane permeability, spreadability and adhesion can each havesignificant effects on permeability.

Delivering an active agent into or through the skin in sufficientconcentrations usually requires some means for reducing the stratumcorneum's hindrance to ingress of the active agent. A number of physicalmethods for lowering the stratum corneum's barrier properties have beendeveloped including electrically assisted techniques such asiontophoresis or electroporation, ultrasound, heat, puncturing thestratum corneum with microneedle arrays, or ablation. Even for a single,non-repeated application such physical methods have limitations, leadingto very restricted use by patients in practice.

SUMMARY

Some embodiments provide for a topical formulation comprisingmultiplexed molecular penetration enhancers for topical or transdermaladministration of a zwitterionic pharmaceutical agent. In someembodiments, the present disclosure relates to a topical formulationcomprising multiplexed molecular penetration enhancers for topical ortransdermal administration of a gabapentinoid. In some embodiments, thepresent disclosure relates to a topical formulation comprisingmultiplexed molecular penetration enhancers for topical or transdermaladministration of pregabalin.

In another of its aspects, the present disclosure provides a topicalformulation for use in topical or transdermal administration of asubstance comprising: (i) at least one active agent, (ii) DMSO, (iii) aketo acid, and (iv) a fatty acid ester.

In another of its aspects, the present disclosure provides a topicalformulation comprising: (i) at least one active agent, (ii) water, (iii)dimethyl sulfoxide (“DMSO”), (iv) a keto acid, and (v) an ester of afatty alcohol and an α-hydroxy acid, an ester of a fatty acid and analcohol, or a mixture thereof.

In another of its aspects, the present disclosure provides a topicalformulation comprising: (i) at least one active agent, (ii) water, (iii)DMSO, (iv) a keto acid, and (v) a fatty alcohol.

In another of its aspects, the present disclosure provides a topicalformulation for use in topical or transdermal administration of asubstance comprising: (i) at least one active agent, (ii) DMSO, (iii)levulinic acid, and (iv) lauryl lactate.

In another of its aspects, the present disclosure provides a topicalformulation for use in topical or transdermal administration of asubstance comprising: (i) at least one active agent, (ii) DMSO, (iii) aketo acid, (iv) a fatty acid ester, and (v) a polyalkylene glycol alkylether.

In another of its aspects, the present disclosure provides a topicalformulation for use in topical or transdermal administration of asubstance comprising: (i) at least one active agent, (ii) DMSO, (iii)levulinic acid, (iv) lauryl lactate, and (v) a polyethylene glycol alkylether.

In another of its aspects, the present disclosure provides a topicalformulation for use in topical or transdermal administration of asubstance comprising: (i) at least one active agent, (ii) DMSO, (iii)levulinic acid, (iv) lauryl lactate, and (v) dimethyl isosorbide.

In another of its aspects, the present disclosure provides a topicalformulation for use in topical or transdermal administration of asubstance comprising: (i) at least one active agent, (ii) DMSO, (iii) afatty alcohol or a fatty acid ester, and (iv) a polyalkylene glycolalkyl ether.

In another of its aspects, the present disclosure provides a topicalformulation for use in topical or transdermal administration of asubstance comprising: (i) at least one active agent, (ii) DMSO, (iii)oleyl alcohol, and (iv) a polyalkylene glycol alkyl ether.

In another of its aspects, the present disclosure provides a topicalformulation for use in topical or transdermal administration of asubstance comprising: (i) at least one active agent, (ii) DMSO, (iii)lauryl lactate, and (iv) a polyalkylene glycol alkyl ether.

In another of its aspects, the present disclosure provides a topicalformulation comprising: (i) at least one active agent, (ii) DMSO, (iii)a fatty alcohol or a fatty acid ester, (iv) a polyalkylene glycol alkylether, and (v) a keto acid.

In another of its aspects, the present disclosure provides a topicalformulation comprising: (i) at least one active agent, (ii) DMSO, (iii)a fatty alcohol or a fatty acid ester, (iv) a polyalkylene glycol alkylether, and (v) levulinic acid.

In another of its aspects, the present disclosure provides a topicalformulation comprising: (i) at least one active agent, (ii) DMSO, and(iii) a plurality of polyalkylene glycol alkyl ethers.

In one aspect, the at least one active agent is a zwitterionic activeagent. In one aspect, the at least one active agent is a gabapentinoid.

Some embodiments provide for a topical formulation suitable forconcentrating a zwitterionic active agent in dermal tissue comprising:(i) at least one zwitterionic active agent, (ii) water, (iii) DMSO, (iv)a keto acid, and (v) an ester of a fatty alcohol and an α-hydroxy acid,an ester of a fatty acid and an alcohol, or a mixture thereof.

In another of its aspects, the present disclosure provides a topicalformulation suitable for concentrating a zwitterionic active agent indermal tissue comprising: (i) at least one zwitterionic active agent,(ii) water, (iii) DMSO, (iv) a keto acid, and (v) a fatty alcohol.

Some embodiments provide for a topical formulation for use in topical ortransdermal administration of pregabalin comprising: (i) pregabalin,(ii) DMSO, (iii) a keto acid, and (iv) a fatty acid ester.

In another of its aspects, the present disclosure provides a topicalformulation comprising: (i) pregabalin, (ii) water, (iii) DMSO, (iv) aketo acid, and (v) an ester of a fatty alcohol and an α-hydroxy acid, anester of a fatty acid and an alcohol, or a mixture thereof.

In another of its aspects, the present disclosure provides topicalformulation comprising: (i) pregabalin, (ii) water, (iii) DMSO, (iv) aketo acid, and (v) a fatty alcohol.

In another of its aspects, the present disclosure provides a topicalformulation for use in topical or transdermal administration ofpregabalin comprising: (i) pregabalin, (ii) DMSO, (iii) levulinic acid,and (iv) lauryl lactate.

In another of its aspects, the present disclosure provides a topicalformulation for use in topical or transdermal administration ofpregabalin comprising: (i) pregabalin, (ii) DMSO, (iii) a keto acid,(iv) a fatty acid ester, and (v) a polyalkylene glycol alkyl ether.

In another of its aspects, the present disclosure provides a topicalformulation for use in topical or transdermal administration ofpregabalin comprising: (i) pregabalin, (ii) DMSO, (iii) levulinic acid,(iv) lauryl lactate, and (v) a polyethylene glycol alkyl ether.

In yet another of its aspects, the present disclosure provides a methodfor treating a subject suffering from pain, said method comprising theadministration to an area of skin of said subject a therapeuticallyeffective amount of formulation comprising: (i) pregabalin, (ii) DMSO,(iii) a keto acid, and (iv) a fatty acid ester, thereby preventing orameliorating said pain.

In yet another of its aspects, the present disclosure provides a topicalformulation comprising a therapeutically active agent, a therapeuticallyacceptable carrier and a skin molecular penetration enhancer, whereinthe skin molecular penetration enhancer consists essentially of amixture of (i) DMSO, (ii) a keto acid and (iii) a fatty acid ester.

In yet another of its aspects, the present disclosure provides a methodfor treating a subject suffering from pain, said method comprising thetopical administration to said subject of a therapeutically effectiveamount of formulation comprising: (i) pregabalin, (ii) DMSO, (iii) aketo acid, and (iv) an ester of a fatty alcohol and an α-hydroxy acid,an ester of a fatty acid and an alcohol, or a mixture thereof. In someembodiments, the topical administration of the formulation prevents orameliorates said pain.

In yet another of its aspects, the present disclosure provides a methodfor treating a subject suffering from pain, said method comprising thetopical administration to said subject of a therapeutically effectiveamount of formulation comprising: (i) at least one zwitterionic activeagent, (ii) water, (iii) DMSO, (iv) a keto acid and (v) an ester of afatty alcohol and an α-hydroxy acid or a fatty alcohol, therebypreventing or ameliorating said pain. In some embodiments, the topicaladministration of the formulation prevents or ameliorates said pain.

These and other objects, aspects, and embodiments will become moreapparent when read with the following detailed description and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates enhancement ratios, computed as the ratios ofcumulative amounts of pregabalin that are found to permeate throughhuman skin over a 4 hour period from the formulations of Example 1(Tables 1-5) relative to that measured in the same experiment fromformulation TrPg201 (Table 1).

FIG. 2 illustrates enhancement ratios, computed as the ratios ofcumulative amounts of pregabalin that are found to permeate throughhuman skin over a 22 hour or 24 hour period from the formulations ofExample 1 (Tables 1-5) relative to that measured in the same experimentfrom formulation TrPg201 (Table 1).

FIG. 3 illustrates enhancement ratios, computed as the ratios of amountsof pregabalin that are found to be retained in human epidermal tissue 22hour or 24 hour after formulation application from the formulations ofExample 1 (Tables 1-5) relative to that measured in the same experimentfrom formulation TrPg201 (Table 1).

FIG. 4 illustrates enhancement ratios, computed as the ratios of amountsof pregabalin that are found to be retained in human dermal tissue 22hour or 24 hour after formulation application from the Example 1formulations (Tables 1-5) relative to that measured in the sameexperiment from formulation TrPg201 (Table 1). The blank columns atright indicate that the corresponding data were not measured.

FIG. 5A to FIG. 5C illustrates cumulative amounts of pregabalin that arefound to permeate through human skin (FIG. 5C) and to be retained inhuman epidermal tissue (FIG. 5A) and in human dermal tissue (FIG. 5B)over a period of 20 or 24 hours from the formulations of Table 1 (thenumbers for formulations TrPg200 and TrPg201 represent unweightedaverages of results from, respectively, two and four independent runsaccording to the procedure of Example 3).

FIG. 6A to FIG. 6C illustrates cumulative amounts of pregabalin that arefound to permeate through human skin (FIG. 6C) and to be retained inhuman epidermal tissue (FIG. 6A) and in human dermal tissue (FIG. 6B)over a 22 hour period from formulations of Table 2 (dermal retentionnumbers were not measured for formulations TrPg218 and TrPg219; thenumbers for formulation TrPg210 represent unweighted averages of resultsfrom three independent runs according to the procedure of Example 3).

FIG. 7A to FIG. 7C illustrates cumulative amounts of pregabalin that arefound to permeate through human skin (FIG. 7C) and to be retained inhuman epidermal tissue (FIG. 7A) and in human dermal tissue (FIG. 7B)over a 22 hour period from the formulations of Table 3 (dermal retentionnumbers were not measured for formulation TrPg220; the numbers forformulation TrPg210 represent unweighted averages of results from threeindependent runs according to the procedure of Example 3).

FIG. 8A to FIG. 8C illustrates cumulative amounts of pregabalin that arefound to permeate through human skin (FIG. 8C) and to be retained inhuman epidermal tissue (FIG. 8A) and in human dermal tissue (FIG. 8B)over a period of 20 or 22 hours from the formulations of Table 4 (dermalretention numbers were not measured for formulations TrPg217 andTrPg219).

FIG. 9A to FIG. 9C illustrates cumulative amounts of pregabalin that arefound to permeate through human skin (FIG. 9C) and to be retained inhuman epidermal tissue (FIG. 9A) and in human dermal tissue (FIG. 9B)over a 22 hour period from the formulations of Table 5 (the numbers forformulation TrPg210 represent unweighted averages of results from threeindependent runs according to the procedure of Example 8).

FIG. 10A to FIG. 10D illustrates cumulative amounts of pregabalin thatare found to permeate through human skin over a 4 hour period (FIG. 10C)and over a 24 hour period (FIG. 10D) and to be retained over a 24 hourperiod in human epidermal tissue (FIG. 10A) and in human dermal tissue(FIG. 10B) from the formulations described in Table 6.

DETAILED DESCRIPTION

Other than physical methods, it is well known in the art that variousfactors can affect the permeation and absorption of an active agent froma skin-applied pharmaceutical preparation, including the nature of theactive, the nature of the vehicle, the pH, and the relative solubilityof the active in the vehicle versus the skin. More specifically, activeattributes such as molecular weight, lipophilicity or hydrophilicity,solubility, size and charge, melting point, as well as vehicleattributes such as active solubility and dissolution rate, ability tomodulate the permeability of the stratum corneum, and physicalcharacteristics such as occlusivity, spreadability and adhesion, and caneach have significant effects on permeability.

Molecular or chemical penetration enhancers can provide an effective andinexpensive means of temporarily reducing skin resistance to the passageof actives and other molecules. Molecular penetration enhancers or“MPE™”s can enhance the diffusion of molecules across the skin by, forexample, disrupting the lipid bilayers of the stratum corneum.

Over 300 substances have been identified as MPE™s but few have beendeveloped successfully into commercial formulations. Many potentenhancers are irritating to the cells of the epidermis which can limitboth the choice and concentration of MPE™s suitable for topicalformulations. Discovery of new MPE™s to increase skin permeability isdesirable and has been an area of high activity over the last 30 years.However, the number of substances identified to be penetration enhancersis still tiny relative to the more than 127,000,000 substancesidentified in the CAS registry (Chemical Abstracts Service, Columbus,Ohio, www.cas.org). Further, for use in a drug product the excipients ina formulation should not introduce fresh safety or other regulatoryconcerns. It is therefore preferable that the choices of excipients belimited to those that are provided in the US Food and DrugAdministration (“FDA”) inactive ingredient database (“IID”).

The number of candidate drugs suitable for topical and transdermaladministration could be significantly increased with improved approachesto molecular penetration enhancement. Notably, it is now realized thatthe best permeation enhancement is typically found with combinations ofMPE™s, rather than by use of individual MPE™s alone. Further, thepenetration enhancing roles of neither individual MPE™s nor of MPE™combinations can be predicted.

Currently only two drugs for administration to the skin with aperipheral mode of action and little to no systemic activity, arecurrently FDA approved and recommended by authorities to treatperipheral neuropathic pain, namely a topical lidocaine patch 5%(Lidoderm®) and a topical capsaicin patch 8% (Qutenza®). This is despitea substantial and protracted global research effort. Even while suchprograms have yet to be successful, they serve as evidence of the majorneed for a novel way to treat peripheral neuropathic pain through askin-applied administration route.

Additionally, literature data support a peripheral action forgabapentinoids. Analgesic effects on peripheral nociception in rats aredemonstrated following administration of injectable gabapentin and theseanti-hyperalgesic properties were shown not to be due to a systemiceffect. Gabapentin has been postulated to offer a novel therapeuticoption for local treatment of pain of peripheral origin.

Despite the appeal of an effective skin-applied formulation of agabapentinoid, the art teaches little on development of suchskin-applied formulations. Both gabapentin and pregabalin arezwitterionic (a zwitterion is a chemical compound that is electricallyneutral through a net cancellation of formal positive and negativecharges at different locations in the molecule) and have a very lowintrinsic skin permeabilities.

Zwitterionic drugs have poor absorption through intact skin due to theirrather large dipole moments and their resulting low lipid solubility.Non-zwitterionic acidic or basic substances can be placed in transdermalformulations at appropriate pH-values such that the active agent issubstantially in the non-ionic form, leading to enhanced absorptionthrough skin. Zwitterionic drugs cannot be made non-ionic. At allpH-values, at least one ionic group is present. For example, atpH-values higher than the pKa of the acidic group(s) of a zwitterion,the acidic group is charged; at pH-values lower than the pKa of thebasic group(s) of a zwitterion, the basic group is charged. At pH-valuesclose to the zwitterion isoelectric point (“pI”), both groups arecharged. Amino acid containing drugs, being zwitterions of greatinterest, remain charged at all pH-values in the range of 2.0 to 11,spanning the pH-range that is suitable for transdermal application. Itwould not be expected that one could achieve a suitable flux of azwitterion through the skin to make transdermal administration thereofpractical.

A gabapentin paste (made by combining gabapentin in ethoxy diglycol witha commercial chassis, namely Lipoderm base (PCCA, Houston, Tex.)),prepared at 2%, 4%, or 6% strengths, is described; from a study ofapplication to postmenopausal women patients it was concluded thattopical gabapentin was well tolerated and associated with significantpain relief. Case reports teach the use of topical gabapentin formulatedby pharmacists in conjunction with other pharmaceutical actives.Pregabalin has been administered rectally with anecdotal success.Applications of a topical gabapentin gel to alleviate allodynia andhyperalgesia in the chronic sciatic nerve constriction injuryneuropathic pain model in rats by a topical gabapentin gel, to relievepostherpetic neuralgia, and to alleviate mechanical allodynia andvulvodynia in a rat model of streptozotocin-induced diabetic neuropathicnociception have each been reported.

A topical pregabalin formulated in a non-active vehicle of pluroniclecithin organogel and an anhydrous gel base was previously described;testing in a rat model of such a formulation at a 10% pregabalinstrength provided a significant reduction of pain as well assignificantly decreased pregabalin plasma levels as compared to thesystemic treatment, suggesting both its efficacy and a peripheral modeof action. Preparation of niosomes (non-ionic surfactant-based vesicles)entrapping pregabalin were previously prepared and reportedly exhibitedpregabalin fluxes of up to 117 μg cm⁻² h⁻¹ through excised rat skin at37±0.5° C. Permeation of pregabalin through shaved abdominal rat skinfrom matrix type transdermal pregabalin patches, ostensibly over up to30 days, has also been reported. The impact of transdermaladministration of pregabalin from a simple aqueous pregabalin solutionpain thresholds in rats has also been studied. Others have observed thattopical treatment with 10% pregabalin or 5% diclofenac formulationsimpacts neuropathic orofacial pain in rats significantly. While humanskin is dramatically less permeable than rodent skin, preventing anextrapolation of any of these reports to prospective performance inhumans, these studies do underscore the interest in topical andtransdermal formulations of gabapentinoids.

In light of the foregoing, there is a need for a formulation suitablefor skin administration that can provide more substantial levels ofdelivery of a zwitterionic pharmaceutical gabapentinoid into and throughthe skin of a subject.

The present disclosure satisfies these and other needs. It hassurprisingly and unexpectedly been discovered that certain combinationsof compounds are excellent molecular penetration enhancers forpregabalin and for other active agents and, as such, can be incorporatedin a topical formulation to facilitate administration of pregabalin orof one or more other active ingredients. The increased penetrationenhancement can also lead to a reduction in the total concentration ofskin irritants in a formulation.

I. Definition of Terms

The terms “a,” “an,” or “the” as used herein not only include aspectswith one member, but also includes aspects with more than one member.For example, an embodiment including “a cellulosic thickening agent anda lower monohydric alcohol” should be understood to present certainaspects with at least a second cellulosic thickening agent, at least asecond lower monohydric alcohol, or both. An embodiment including “anactive agent” should be understood to present certain aspects with atleast a second active agent, which may be of a different class (e.g., anon-steroidal anti-inflammatory drug with an anti-inflammatory steroidor a local anesthetic).

The term “about” as used herein to modify a numerical value indicates adefined range around that value. If “X” were the value, “about X” wouldgenerally indicate a value from 0.95X to 1.05X. Any reference to “aboutX” specifically indicates at least the values X, 0.95X, 0.96X, 0.97X,0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, “about X” isintended to teach and provide written description support for a claimlimitation of, e.g., “0.98X”. When the quantity “X” only includeswhole-integer values (e.g., “X carbons”), “about X” indicates from (X−1)to (X+1). In this case, “about X” as used herein specifically indicatesat least the values X, X−1, and X+1. When “about” is applied to thebeginning of a numerical range, it applies to both ends of the range.Thus, “from about 5 to 20%” is equivalent to “from about 5% to about20%.” When “about” is applied to the first value of a set of values, itapplies to all values in that set. Thus, “about 7, 9, or 11%” isequivalent to “about 7%, about 9%, or about 11%.”

In compositions comprising an “additional” or “second” component, thesecond component as used herein is chemically different from the othercomponents or first component. A “third” component is different from theother, first, and second components, and further enumerated or“additional” components are similarly different.

“Agent” as used herein indicates a compound or mixture of compoundsthat, when added to a pharmaceutical composition, tend to produce aparticular effect on the said composition's properties. For example, acomposition comprising a thickening agent is likely to be more viscousthan an otherwise identical comparative composition that lacks thethickening agent.

“Cellulosic thickening agent” as used herein includes a thickening agentthat is a natural or synthetic polymeric carbohydrate (e.g., celluloseand pharmaceutically acceptable vegetable gums) or a polymeric oroligomeric derivative of a polymeric carbohydrate that is produced bychemical modification (e.g., hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose). Representative cellulosicthickening agents include cellulose, hydroxypropyl cellulose (“HPC”),hydroxypropyl methyl cellulose (“HPMC”), hydroxyethyl cellulose (“HEC”),methyl cellulose, carboxymethyl cellulose, and the like.

The terms “chassis,” “vehicle” and “base formulation” as usedinterchangeably herein are equivalent terms that include a plurality ofsolvents or other excipients that comprise the bulk of a formulation,into which one or more active agents or additional components might beintroduced.

As used herein, the phrase “effective amount” or “effective dose” meansan amount sufficient to achieve the desired result and accordingly willdepend on the ingredient and its desired result. Nonetheless, once thedesired effect is known, determining the effective amount is within theskill of a person skilled in the art.

“Enhancement ratio” or “ER” as used interchangeably herein is the ratioof a test result (e.g., accumulated dose of product expressed in μgcm⁻²) from a formulation comprising an active to the corresponding testresult from a control composition comprising the same active at the sameconcentration in the formulation.

In general, the “error bars” on the graphs represent the standard errorof the mean value, whereas the top of the solid, shaded bar represents asingle data value, which is the mean value of the distribution of datavalues.

“Finite dosing” as used herein generally includes an application of alimited reservoir of an active agent. The active agent in the reservoiris depleted with time, leading to a decrease of the absorption rateafter a maximum rate is reached.

“Formulation,” “pharmaceutical composition,” and “composition” as usedinterchangeably herein are equivalent terms referring to a compositionof matter for pharmaceutical use.

“Local delivery” as used herein means delivery of an agent into theskin; in the literature such local delivery is frequently referred to as‘topical delivery.’

The prefix “micro” as used herein can be alternatively abbreviated as“μ” or “u.” For example, micrograms are typically abbreviated as μg, butcan alternatively be abbreviated as “ug”.

“Monohydric alcohol” as used herein includes straight- or branched-chainalkyl alcohols with a single hydroxyl group. Representative monohydricalcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol,t-butanol, n-pentanol, 3-pentanol, 2-methoxyethanol,2-(2-ethoxyethoxy)ethanol (transcutol), oleyl alcohol, and the like.

As used herein the term “multiplexed molecular penetration enhancer” or“MMPE™” means a molecular penetration enhancer comprising two or moresubstances wherein each of the two or more substances is also amolecular penetration enhancer.

The term “or” as used herein should in general be construednon-exclusively. For example, an embodiment of “a composition comprisingA or B” would typically present an aspect with a composition comprisingboth A and B. “Or” should, however, be construed to exclude thoseaspects presented that cannot be combined without contradiction (e.g., acomposition pH that is between 9 and 10 or between 7 and 8).

“Penetration enhancer,” “molecular penetration enhancer” or “MPE™” asused herein includes an agent or a combination of agents that improvesthe transport of molecules such as a pharmaceutically or cosmeticallyactive agent into or through a natural membrane such as skin or nail.Various conditions may occur at different sites in the body, either inthe skin or below the skin, creating a need to target delivery ofcompounds. For example, in products designed to produce artificial tansdelivery of a dye substance into the stratum corneum may beadvantageous. A psoriasis treatment on the other hand may requiredelivery of therapeutic drug levels into deeper epidermal tissue. In atreatment for osteoarthritis delivery of the active agent into deeperunderlying joint tissue may be necessary to achieve therapeutic benefit.In yet other applications, for example in hormone replacement therapy,delivery of drug to the systemic circulation may be an objective. Thus,a “molecular penetration enhancer” may be used to assist in the deliveryof an active agent directly to the skin or underlying tissue orindirectly to the site of the disease through systemic distribution. Ifsystemic distribution of an active agent (e.g., pregabalin) would belikely to produce side effects, a molecular penetration enhancer isselected to maximize direct delivery and to minimize systemicdistribution. A penetration enhancer may be a pure substance or maycomprise a mixture of different chemical entities. In this specificationthe terms “penetration enhancer,” “chemical penetration enhancer,”“molecular penetration enhancer,” and “MPE™” or “MPE” are usedinterchangeably.

The term “pH adjusting agent” as used herein refers to a compound addedto a composition as described herein for the purpose of changing the pHof the composition. Examples of such agents include pharmaceuticallyacceptable acids, pharmaceutically acceptable bases, andpharmaceutically acceptable buffers.

The term “pharmaceutically acceptable” means compatible with thetreatment of animals, and in particular, humans.

The term “pharmaceutically acceptable salt” means a pharmaceuticallyacceptable acid addition salt or a pharmaceutically acceptable baseaddition salt. The formation of a desired compound salt is achievedusing standard techniques. For example, the neutral compound is treatedwith an acid or base in a suitable solvent and the formed salt isisolated by filtration, extraction, or any other suitable method.

“Regional delivery” as used herein means delivery of an agent throughthe skin but concentrating in proximal tissue or joint.

The term “subject” as used herein includes all members of the animalkingdom, preferably mammals, and most preferably, humans.

“Superficial delivery” as used herein means delivery of an agent to theskin exterior surface only.

“Surfactant” as used herein includes a surface-active agent. Surfactantsreduce the surface tension of a solvent in which they are dissolved.

“Thickening agent” as used herein includes an agent or combination ofagents that increases the viscosity of a composition. A thickening agentmay be a pure substance, or it may comprise, consist essentially of, orconsist of a mixture of different chemical entities. Exemplarythickening agents include cellulosic thickening agents, otherpolysaccharides such as chitosan and the like, carbomer polymers,carbomer derivatives, polyvinyl alcohol, poloxamers, as well as mixturesthereof.

“Topical formulation” as used herein includes a composition that issuitable for topical application to the skin, nail, or mucosa. A topicalformulation may, for example, be used to confer a therapeutic orcosmetic benefit to its user. Specific topical formulations can be usedfor superficial, local, regional, or transdermal delivery of substances.

The term “topical administration” is used in its conventional sense tomean delivery of a substance, such as a therapeutically active agent, tothe skin or to a localized region of the body.

Topical administration of a drug may often be advantageously applied in,for example, the treatment of various skin disorders.

“Transdermal” as used herein includes a process that occurs through theskin. The terms “transdermal,” “percutaneous,” and “transcutaneous” canbe used interchangeably. In certain embodiments, “transdermal” may alsoinclude epicutaneous.

“Transdermal application” or “transdermal administration” as usedinterchangeably herein are equivalent terms that include administrationthrough the skin. Transdermal application can be used for systemicdelivery of an active agent. In certain embodiments, “transdermalapplication” may also include epicutaneous application.

The term “treating” or “treatment” as used herein (and as wellunderstood in the art) means an approach for obtaining beneficial ordesired results in a subject's condition, including clinical results.Beneficial or desired clinical results can include, but are not limitedto, alleviation or amelioration of one or more symptoms or conditions,diminishment of the extent of a disease, stabilizing (i.e., notworsening) the state of disease, prevention of a disease's transmissionor spread, delaying or slowing of disease progression, amelioration orpalliation of the disease state, diminishment of the reoccurrence ofdisease, and remission, whether partial or total and whether detectableor undetectable. “Treating” and “treatment” as used herein also includeprophylactic treatment. Treatment methods comprise administering to asubject a therapeutically effective amount of an active agent. Theadministering step may consist of a single administration or maycomprise a series of administrations. The compositions are administeredto the subject in an amount and for a duration sufficient to treat thepatient. The length of the treatment period depends on a variety offactors, such as the severity of the condition, the age of the patient,the concentration of active agent, the activity of the compositions usedin the treatment, or a combination thereof. It will also be appreciatedthat the effective dosage of an agent used for the treatment orprophylaxis may increase or decrease over the course of a particulartreatment or prophylaxis regime. Changes in dosage may result and becomeapparent by standard diagnostic assays known in the art. In someinstances, chronic administration may be required.

The term “w/w” or “wt/wt” means a percentage expressed in terms of theweight of the ingredient or agent over the total weight of thecomposition multiplied by 100.

II. Constituents A. Active Agent

The present disclosure provides for compositions and formulationscomprising at least one active agent.

In one aspect, the at least one active agent is a zwitterionic activeagent. Non-limiting examples of zwitterionic active agents include(4-{2-[2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)-ethylamino]-propyl}-phenoxy)-aceticacid;(Z)-4-[(2-{[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-2-pyridinyl]methoxy}ethyl)amino]-4-oxo-2-butenoicacid; 2-(cyclohexylamino)ethanesulphonic acid (“CHES”);2(N-morpholino)ethanesulphonic acid (“MES”);2-azabicyclo-[3.3.0]-octane-3-carboxylic acids; 3-(cyclohexylamino)propanesulphonic acid (“CAPS”); 3-(N-morpholino)propanesulphonic(“MOPS”); 4-amino-3-phenylbutyric acid;7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid; amino acids such as L-tyrosine or peptides; baclofen;benazeprilat; cefaclor; cefalexine; cefatrizine; cefdinir; cefepine;cefixime; cefpodoxime; cefroxadine; ceftriaxone; cephalosporin;cetirizine; cis, endo-2-azabicyclo-[3.3.0]-octane-3-carboxylic acids;cyclopropyl-8-(difluoromethoxy)-7-[(1R)-1-methyl-2,3-dihydro-1H-5-isoind-olyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate monohydrate (bis-quinolone); diiodotyrosine;fexofenadine; gabapentin; heterocyclic selenates; L-dopa;levocetirizine; levothyrosine; libenzapril; liothyronin; melphalen;metirosine; N-(2-acetamido) iminodiacetic acid (“ADA”);N-(2-acetamido)-2-aminoethanesulphonic acid (ACES);N,N-bis(2-hydroxyethyl)-2-aminoethanesulphonic acid (“BES”);N-2-hydroxyethylpiperazine-N′-2-ethanesulphonic acid (“HEPES”);N-2-hydroxyethylpiperazine-N′3-propanesulphonic acid ((H)EPPS);N—N[tris(hydroxymethyl)-methyl]-2-aminoethanesulphonic acid (“TES”);ofloxacin; p-aminosalicyclic acid; piperazine-N,N′ bis(2-ethanesulphonicacid (“PIPES”); piro-2-aza-alkane-3-carbonitriles per U.S. Pat. No.4,515,960; pregabalin; salicylates, such as choline-magnesiumsalicylate; taurine (2-aminoethanesulphonic acid); α-methyldopa; andγ-aminobutyric acid (“GABA”). In some embodiments, the zwitterionicactive agent is a gabapentinoid.

In some embodiments, the at least one active agent is an aryl alkanoicacid.

In one embodiment, the at least one active agent is a pharmaceuticalagent, a cosmeceutical agent, a cosmetic agent, a nutritionalsupplement, a vitamin, a diagnostic agent, or an ink or colorant.

In one aspect, the at least one active agent is a gabapentinoid, thatis, a 3-substituted derivative of the neurotransmitter GABA which blocksthe α2δ subunit-containing voltage-dependent calcium channels (“VDCC”s).Non-limiting examples of gabapentinoids include gabapentin, pregabalin,mirogabalin, atagabalin, 4-methylpregabalin, F-phenibut, phenibut andPD-217,014. Also included are gabapentin prodrugs, such as gabapentinenacarbil. In some embodiments, the gabapentinoid is gabapentin,pregabalin, mirogabalin, atagabalin, 4-methylpregabalin and PD-217,014.

Gabapentin and pregabalin selectively interact with the α2δ subunit ofvoltage-dependent calcium channels (“VDCC”s) in the central nervoussystem. Gabapentin and pregabalin decrease the release ofneurotransmitters such as glutamate, noradrenaline, and substance P, andincrease neuronal γ-aminobutyric acid (“GABA”) levels by producing adose-dependent increase in glutamic acid decarboxylase activity.Gabapentin and pregabalin have potential in treatment of chronicpruritis. Gabapentin and pregabalin are also anticonvulsants. Astransdermal administration is a very convenient modality and as patientcompliance for transdermal administration surpasses those for othermodalities, a formulation able to deliver gabapentin or pregabalintransdermally would be especially desired. Further, pregabalin has sideeffects when taken orally such as dizziness, sleepiness, dry mouth,blurred vision, difficulty with concentration, hyper-sensitivity anddecreased platelet count; severe flatulence is also a known side effectof oral pregabalin.

In some embodiments, the active agent is a gabapentinoid. In someembodiments, the active agent is gabapentin or pregabalin. In oneaspect, the active agent is pregabalin. In one aspect, the active agentis gabapentin.

The structures of pregabalin and gabapentin are shown below.

In one aspect, the at least one active agent is an anti-inflammatoryagent. In some embodiments, the at least one active agent is anon-steroidal anti-inflammatory drug (“NSAID”).

Non-limiting examples of NSAIDs include acetic acid derivatives such asindomethacin, sulindac, etodolac, and diclofenac; propionic acidderivatives such as pregabalin, naproxen, fenoprofen, ketoprofen,fluriprofen, and oxaprozin; coxibs such as celecoxib, rofecoxib,valdecoxib, parecoxib, lumiracoxib, and etoricoxib; fenamic acidderivatives such as mefenamic acid, meclofenamic acid, flufenamic acid,and tolfenamic acid; enolic acid derivatives such as piroxicam,meloxicam, tenoxicam, droxicam, and isoxicam; and the compounds'pharmaceutically acceptable salts such as diclofenac sodium, naproxensodium, and diclofenac potassium and the like. In some embodiments, theNSAID is an acetic acid derivative or a pharmaceutically acceptable saltthereof, or a coxib or a pharmaceutically acceptable salt thereof. OtherNSAIDs include aspirin, salicylic acid, diflunisal, etodolac,nabumetone, salsalate, and their pharmaceutically acceptable salts.

In some embodiments, the at least one active agent is an NSAID selectedfrom the group consisting of acetaminophen (paracetamol), aspirin,celecoxib, diflunisal, etoricoxib, piroxicam, salsalate and rofecoxib,and pharmaceutically acceptable salts and solvates thereof, and mixturesthereof.

In some embodiments, the at least one active agent is a phenethylamine.In some embodiments, the active agent is a steroid.

An embodiment including “an active agent” should be understood topresent certain aspects with at least a second active agent, which maybe the same class or a different class (e.g., a gabapentinoid with anon-steroidal anti-inflammatory drug, or with an anti-inflammatorysteroid, or with a local anesthetic).

Accordingly, in some embodiments, the formulations described hereincomprise a combination of active agents, wherein the active agents areas described herein.

B. Dimethyl Sulfoxide (“DMSO”)

In one aspect, the compositions and formulations comprise DMSO. DMSO isa polar aprotic solvent characterized as having low surface tension.DMSO permeates readily through skin and is known to function in someinstances as a penetration enhancer. For example, while pharmaceuticalcompositions comprising DMSO have been reported, preferred embodiments,in certain of these cases comprise 50% w/w or higher of DMSO.

In the present disclosure, the DMSO may be present in an amount of 10%to 40% w/w. In some embodiments, DMSO is present in an amount of atleast 12% w/w. In some embodiments, DMSO is present in an amount of atleast 15% w/w. In some embodiments, DMSO is present in an amount ofabout 15-20% w/w. In a particular embodiment of the disclosure, DMSO isused at a concentration of about 12 to 20% w/w, such as 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 and 35 w/w as well as allfractions in between such as 22.5, 23.5, 24.5, 25.5, and the like.

C. Keto Acid

In one aspect, the compositions and formulations comprise a keto acid.

In the present disclosure the keto acid may be an alpha-keto acid (alsoknown as “aka” a 2-oxoacid), such as pyruvic acid or oxaloacetic acid, abeta-keto acid (aka a 3-oxoacid), such as acetoacetic acid, or agamma-keto acid (aka a 4-oxoacid), such as levulinic acid. In someembodiments, the keto acid is a gamma-keto acid. In some embodiments,the gamma-keto acid is levulinic acid.

In some embodiments, the keto acid is levulinic acid. Levulinic acid ispresent in an amount of up to about 10% w/w. In some embodiments,levulinic acid is present in an amount of up to about 5% w/w. In someembodiments, levulinic acid is present in an amount of up to about 2%w/w.

D. Fatty Acid Ester

In one aspect, the compositions and formulations comprise a fatty acidester.

In the present disclosure, the fatty acid ester may be an esterresulting from the combination of a saturated fatty acid (such as,without limitation, caprylic acid, capric acid, lauric acid, myristicacid, palmitic acid, stearic acid, arachidic acid or behenic acid) or anunsaturated fatty acid (such as, without limitation, myristoleic acid,palmitoleic acid, sapienic acid, oleic acid, erucic acid, elaidic acid,vaccenic acid, linoleic acid, linoelaidic acid, α-linolenic acid,arachidonic acid or eicosapentaenoic acid) with a monohydric, dihydricor trihydric alcohol. In some embodiments, the fatty acid ester is anester resulting from the combination of a fatty acid with a monohydricalcohol. In some embodiments, the fatty acid ester is an ester resultingfrom the combination of a saturated fatty acid with a monohydricalcohol. In some embodiments, the fatty acid ester is an ester resultingfrom the combination of a fatty alcohol with a hydroxy acid. In someembodiments, the fatty acid ester is an ester resulting from thecombination of a saturated fatty alcohol with a hydroxy acid. In someembodiments, the fatty acid ester is an ester resulting from thecombination of a saturated fatty alcohol with an α-hydroxy acid.

In some embodiments, the ester of a fatty alcohol and an α-hydroxy acidis lauryl lactate. In some embodiments, the fatty acid ester is lauryllactate. Lauryl lactate is present in an amount of up to about 10% w/w.In some embodiments, lauryl lactate is present in an amount of up toabout 5% w/w. In some embodiments, lauryl lactate is present in anamount of up to about 3% w/w.

In some embodiments, the fatty acid ester is an ester of a fatty acidand an alcohol. In some embodiments, the ester of a fatty acid and analcohol is isopropyl myristate.

E. Fatty Alcohol

In one aspect, the compositions and formulations comprise a fattyalcohol.

In the present disclosure the fatty alcohol may include 1-octanol (akacapryl alcohol), 1-nonanol (aka pelargonic alcohol), 1-decanol (akacapric alcohol), 1-undecanol (aka undecyl alcohol), 1-dodecanol (akalauryl alcohol), 1-tridecanol, 1-tetradecanol (aka myristyl alcohol),1-pentadecanol (aka pentadecyl alcohol), 1-hexadecanol (aka cetylalcohol), cis-9-hexadecen-1-ol (aka palmitoleyl alcohol), heptadecylalcohol (aka 1-n-heptadecanol), 1-octadecanol (aka stearyl alcohol),cis-9-octadecen-1-ol (aka oleyl alcohol), 1-nonadecanol (aka nonadecylalcohol), 1-eicosanol (aka arachidyl alcohol). In some embodiments, thefatty alcohol is oleyl alcohol. Oleyl alcohol is present in an amount ofup to about 10% w/w. In some embodiments, oleyl alcohol is present in anamount of up to about 5% w/w. In some embodiments, oleyl alcohol ispresent in an amount of up to about 3% w/w.

F. Polyalkylene Glycol Alkyl Ether

In one aspect, the composition or formulation comprises at least onepharmaceutically acceptable surfactant that is a polyalkylene glycolalkyl ether. The polyalkylene glycol alkyl ether may be present at up toabout 7% w/w, such as about 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 1.0, 1.5, 2,2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5 or 7% w/w. In some embodiments, thepolyalkylene glycol alkyl ether is present at up to about 2% w/w, suchas about 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 1.0, 1.25, 1.5, 1.75 or 2% w/w.

In some embodiments, the composition or formulation comprises apolyalkylene glycol alkyl ether. In some embodiments, the composition orformulation comprises polyalkylene glycol alkyl ether such as apolypropylene oxide alkyl ether or a polyethylene glycol alkyl ether.Some non-limiting examples of polyalkylene glycol alkyl ethers includepoly(oxyethylene) cetyl ether, poly(oxyethylene) palmityl ether,polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether,Brij™ 30 (Brij™ L4), Brij 38, Brij 52, Brij 56, Brij 58, Brij 78, Brij98, Brij 700, Brij 700P, Brij 721, Brij S20, and Brij W1. In someembodiments, the polyalkylene glycol alkyl ether is a polyethyleneglycol alkyl ether. In some embodiments, the polyalkylene glycol etheris a Brij polyalkylene glycol alkyl ethers.

Other non-limiting examples include members of the class of alkyl ethernonionic surfactants with two to 100 alkylene glycol repeat units intheir polyalkylene glycol polymeric chains. In some embodiments, thealkyl group is derived from a fatty acid alcohol. In some embodiments,the polyalkylene glycol is polyethylene glycol.

The composition may include a polyalkylene glycol block co-polymer suchas Poloxamer 188 or Poloxamer 407.

G. Alcohol

In one aspect, the compositions and formulations comprise a monohydricalcohol. Suitable monohydric alcohols include, but are not limited to,ethanol, propanol, propan-2-ol, (isopropanol), butanol, butan-2-ol(isobutanol), pentanol, pentan-2-ol, pentan-3-ol, 3-methyl-2-butanol,hexanol, hexan-2-ol, hexan-3-ol, benzyl alcohol,2-(2-Ethoxyethoxy)ethanol (transcutol) and the like, as well as amixture thereof.

In certain aspects, the monohydric alcohol is ethanol or benzyl alcohol.

In one aspect, the compositions and formulations comprise a diol.Suitable diols include, but are not limited to, propylene glycol,butanediol, butynediol, pentanediol, hexanediol, octanediol, neopentylglycol, 2-methyl-1,3-propanediol, diethylene glycol, triethylene glycol,tetraethylene glycol, dipropylene glycol, dibutylene glycol, propyleneglycol, and the like, as well as a mixture thereof. In one aspect, theformulation comprises about 0% to 20% w/w of a diol or about 5 to 15% ofa diol. In certain aspects, the diol is a glycol, such as ethyleneglycol, propylene glycol, or a mixture thereof. In some embodiments, thediol is propylene glycol.

In still another aspect, the composition or formulation includes atleast two alcohols. In some embodiments, the formulation includes amonohydric alcohol and a diol. In some embodiments, the monohydricalcohol is ethanol. Alternatively, the diol is propylene glycol. In someembodiments, the monohydric alcohol is ethanol, and the diol ispropylene glycol.

In one aspect, the compositions and formulations comprise a polyhydricalcohol. Suitable polyhydric alcohols include, but are not limited toglycerol, erythritol, threitol, arabitol, xylitol, ribitol and the like,as well as a mixture thereof.

In certain aspects, the polyhydric alcohol is glycerol (aka glycerin).

H. Additional Molecular Penetration Enhancer (“MPE™”)

In one aspect, the composition or formulation comprises at least oneadditional pharmaceutically acceptable MPE™. Suitable MPE™s include, butare not limited to, 2-amino-2-methyl-1-propanol, butyl alcohol, sodiumlauryl ether(2) sulfate, cetearyl alcohol, chlorobutanol (1,1,1trichloro-2-methyl-2-propanol), chloro-m-cresol,4-chloro-3,5-dimethylphenol (chloroxylenol), disodium cocamphodiacetate,dioctyl phthalate, disodium laureth sulfosuccinate,2-ethyl-1,3-hexanediol, ethyl oleate, ethanol, glyceryl laurate(glycerol monolaurate), glyceryl oleate (glycerol monooleate), glycerylpalmitate (monopalmitin), glyceryl ricinoleate, isopropyl myristate,isopropyl alcohol, lactic acid, lauric diethanolamide, L-a-lecithin,myristyl alcohol (tetradecanol), disodium lauryl sulfosuccinate,menthol, methyl laurate, sodium cocoyl sarcosinate (perlastan c 30),n-lauroyl sarcosine, octyl dodecanol, oleic acid (octadecenoic acid),propylene glycol, propylene glycol diacetate, propylene glycoldicaprylate, phenoxyethanol, sodium dodecyl benzene sulfonate, sodiumlauryl ether sulfate, sodium dodecyl sulfate, sodium laurylsulfoacetate, sodium n-lauroyl sarcosinate, Span 20 (sorbitanmonolaurate), Span 80 (sorbitan monooleate), tertiary butanol,alpha-terpineol, triethanolamine lauryl sulfate, Tween 20 (POE sorbitanmonolaurate), Tween 40 (POE sorbitan monopalmitate), Tween 60 (POEsorbitan monolaurate), Triton x (octoxynol 9), wickenol 143 (oleyloleate), anise oil, laurocapram, benzyl dimethyl dodecyl ammoniumbromide, polyethylene glycol dodecyl ether (PEGE), cocamidopropylbetaine (CBC), cocamidopropyl hydroxysultaine, oleyl betaine, cineole,cetyl trimethyl ammonium bromide, cyclopentadecanolide, dodecyl amine,dodecyl methyl sulfoxide, n-dodecyl-2-pyrrolidone,n-decyl-2-pyrrolidone, dimethyl sulfoxide, dodecyl pyridinium chloride,eucalyptus oil, glyceryl caprylate, glyceryl dilaurate, 1,2 hexanediol,hexadecyl dimethyl ammoniopropane sulfonate, potassium cocoyl hydrolyzedcollagen, lauric acid, lauroylcholine chloride, limonene, linoleic acid,linolenic acid, lauryl lactate, 1-methyl-2-pyrrolidone, methylsalicylate, nicotine sulfate, octyl salicylate, octyl trimethyl ammoniumbromide, poly(ethylene glycol) 300, 1-phenyl piperazine, salicylic acid,sodium cocoyl glutamate, sodium oleate, sodium octyl sulfate, TEA cocoylhydrolyzed collagen, tetracaine, alpha-tocopherol and the like, as wellas a mixture thereof.

In certain aspects, the additional MPE™ is dimethyl isosorbide.

I. Quaternary Ammonium Compound

In one aspect, the composition or formulation comprises at least onepharmaceutically acceptable long-chain quaternary ammonium compound. Thelong-chain quaternary ammonium compound serves as a surfactant andfunctions also as an antimicrobial (as per following). In certainaspects, the quaternary ammonium compound is cetylpyridinium chloride(“CPC”) or cetylpyridinium bromide.

In certain aspects, the quaternary ammonium compound is cetylpyridiniumchloride. The CPC may be present at up to about 7% w/w, such as about0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5,6, 6.5 or 7% w/w. In some embodiments, the CPC is present at up to about2% w/w, such as about 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 1.0, 1.25, 1.5,1.75 or 2% w/w.

J. Water

In certain aspects, the compositions or formulations comprise water. Insome embodiments, water is present from about 10% to 95% w/w such asabout 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90or 95% w/w. In some embodiments, the composition includes from about 10to 20%, about 20 to 40%, about 40 to 50%, about 50 to 60%, about 60 to70%, or about 70 to 95% w/w water. Alternatively, the mixture includesabout 10, 12.5, 15, 17.5, 20 or 25% w/w water.

K. Thickening Agent

In one aspect, the viscosity of the compositions and formulations isadjusted by incorporation of a thickening agent such as a cellulosicthickening agent, another polysaccharide such as chitosan or the like, acarbomer polymer, a carbomer derivative, polyvinyl alcohol, a poloxamer,or a mixture thereof and the like.

The nature of the thickener and the thickener concentration is chosen soas to produce a formulation of the desired viscosity, as is familiar toone skilled in the art.

L. Emollients

Emollients can optionally be added to the compositions or formulationsof the disclosure so that the formulations can maintain or increase themoisture content of the stratum corneum when the composition is appliedto the skin. Emollients may be added to the formulations in addition tothe components already described, which may also aid in maintaining orimproving the skin condition of the user.

In one aspect, added emollients are included in the compositions orformulations of the disclosure at a concentration between about 0.1 and20% w/w. In another aspect, the added emollient can be present in thecomposition at a concentration between about 0.5% and 10% w/w. In stillanother aspect, the emollient concentration can be between about 1% and5% w/w.

Emollients are generally separated into two broad classes based on theirfunction. The first class of emollients functions by forming anocclusive barrier to prevent water evaporation from the stratum corneum.The second class of emollients penetrate into the stratum corneum andphysically bind water to prevent evaporation. The first class ofemollients is subdivided into compounds which are waxes at roomtemperature and compounds which are liquid oils. The second class ofemollients includes those which are water soluble and are often referredto as humectants.

Suitable emollients may be selected from any of the classes known in theart. A general list of useful emollients appears, for example, in U.S.Pat. No. 4,478,853 and in EP patent application 0 522 624A1 as well asin the CTFA Cosmetic Ingredient Handbook published by The Cosmetic,Toiletry, and Fragrance Association, Washington D.C. (1992) under thelistings “Skin Conditioning agents,” “emollients,” “humectants,”“miscellaneous,” and “occlusive.”

In some aspects, emollients may be chosen from the followingnon-limiting list of general emollients, occlusive emollients, andhumectants. Examples of general emollients include short-chain alkyl oraryl esters (C1-C7) of long-chain straight- or branched-chain alkyl oralkenyl alcohols or acids (C8-C32) and their polyethoxylatedderivatives; short-chain alkyl or aryl esters (C1-C7) of C4-C12 diacidsor diols optionally substituted with one or more hydroxyl groups; alkylor aryl C1-C10 esters of glycerol, pentaerythritol, ethylene glycol,propylene glycol, as well as polyethoxylated derivatives of these andpolyethylene glycol; C12-C22 alkyl esters or ethers of polypropylene;C12-C22 alkyl esters or ethers of polypropylene/polyethylene glycolcopolymer.

Non-limiting examples of occlusive emollients include cyclic and lineardimethicones; polydialkylsiloxanes; polyarylalkylsiloxanes; long chain(C8-C36) alkyl and alkenyl esters of long straight or branched chainalkyl or alkenyl alcohols or acids; long chain (C8-C36) alkyl andalkenyl amides of long straight or branched chain (C8-C36) alkyl oralkenyl amines or acids; hydrocarbons including straight and branchedchain alkanes and alkenes such as squalene, squalane and mineral oil;jojoba oil; polysiloxane polyalkylene copolymers; short chain alkyl oraryl esters (C1-C36) of C12-C22 diacids or diols optionally substitutedwith one or more hydroxyl groups such as diisopropyl dimer dilinoleate;and C12-C22 alkyl and alkenyl alcohols; long chain alkyl or aryl esters(C8-C36) of C12-C22 diacids or diols optionally substituted in availablepositions by —OH, such as diisostearyl dimer dilinoleate; lanolin andlanolin derivatives; and beeswax and its derivatives.

Non-limiting examples of humectant-type emollients include glycerol,polyglycerols (including: diglycerol, triglycerol, polyglycerin-3,tetraglycerol, hexaglycerol, decaglycerols), propylene glycol,dipropylene glycol, polypropylene glycol, polyethylene glycol (PEG-2 toPEG-45M, and in some embodiments, a molecular weight between about 300and 1,000), sorbitol, polyhydric alcohol ethoxylates (e.g. sorbeth-6,sorbeth-30, glycereth-1 to glycereth-31), methoxides of polyethyleneglycol (Methoxy PEG-2 to Methoxy PEG-100) methoxides of polyhydricalcohol ethoxylates (e.g. glycereth-7 methoxide), pantothenol, gluconicacid salts and the like. Other humectant-type agents that could also beemployed include: 1,2,6-hexanetriol, acetamide MEA, aluminum hydroxide,arginine PEA, butoxypropanol, butylene glycol, dimethyl imidazolidinone,dimethylsilanol hyaluronate, dipotassium glycyrrhizate, erythritol,ethoxy-diglycol, fructose, glucamine, gluconic acid, glucose, glucoseglutamate, glucuronic acid, glutamic acid, glycogen, glycyrrhizic acid,heilmoor clay, hexacosyl glycol, histidine, hyaluronic acid,hydrogenated honey, hydrogenated starch, hydrolysate, hydrolyzedcollagen, hydrolyzed elastin, hydrolyzed glycosaminoglycans, hydrolyzedkeratin, hydrolyzed silk, hydrolyzed soy protein, hydrolyzed wheatprotein, hydroxyethyl sorbitol, inositol, inositol hexa-PEA, lactamideMEA, lactic acid, lactitol, lactose, lysine PEA, magnesium PEA,maltitol, manganese PEA, mannitol, Mel extract (honey extract), menthylPEA, methyl gluceth-10, methyl gluceth-20, PEA (pidolic acid),lactamide, polydextrose, polyglucuronic acid, polyglyceryl sorbitol,potassium PEA, PPG-20 methyl glucose ether, PPG-38-buteth-37, saccharideisomerate, serica, silk amino acids, sodium carboxymethyl chitin, sodiumlactate, sodium mannuronate methylsilanol, sodium PEA, sodium PEAmethylsilanol, sodium polyglutamate, soluble collagen, sorbitol,sucrose, TEA-lactate, tea-PEA, trehalose, trilactin, urea, xylitol, Zeamays, zinc PEA, and combinations thereof.

The addition of one or more emollients may affect the viscosity andstability of the compositions of the present disclosure. In someembodiments, a single emollient may be added to the composition. Inother embodiments, two or more emollients may be added to thecomposition. While any of a variety of emollients may be added to theformulations of the present disclosure, some embodiments will includewax and oil type emollients either alone or combined with water solubleemollients. In some embodiments of the disclosure, emollient systems canbe comprised of humectants in addition to occlusive wax and oilemollients in concentrations that achieve a moisturizing effect andwhich maintain and improve the condition of the skin upon repeated use.Emollients may be non-comedogenic and chosen to avoid skin irritation orsensitization reactions.

M. Other Components

In one aspect, the composition or formulation additionally comprises ananti-oxidant. Non-limiting examples of anti-oxidants for use in thepresent disclosure include butylated hydroxytoluene, butylatedhydroxyanisole, ascorbyl linoleate, ascorbyl dipalmitate, ascorbyltocopherol maleate, calcium ascorbate, carotenoids, kojic acid and itspharmaceutically acceptable salts, thioglycolic acid and itspharmaceutically acceptable salts (e.g., ammonium), tocopherol,tocopherol acetate, tocophereth-5, tocophereth-12, tocophereth-18, ortocophereth-80.

In one aspect, the composition or formulation additionally comprises atleast one preservative. Non-limiting examples of preservatives for usein the present disclosure include benzalkonium chloride, cetrimoniumbromide (aka cetyltrimethylammonium bromide), cetylpyridinium chloride,benzethonium chloride, alkyltrimethylammonium bromide, methyl paraben,ethyl paraben, propyl paraben, butyl paraben, benzyl alcohol, cetylalcohol, steryl alcohol, benzoic acid, sorbic acid, chloroacetamide,trichlorocarban, thimerosal, imidurea, bronopol, chlorhexidine,4-chlorocresol, 4-chloroxylenol, dichlorophene and hexachlorophene. Insome embodiments, the preservative is cetylpyridinium chloride, methylparaben and propyl paraben, or mixtures thereof.

In still another aspect, the composition or formulation is acidic. Incertain aspects, the composition or formulation has a pH of below about7.5, 6.5, 5.5, 4.5, 3.5, or 2.5. In certain other aspects, the pH ofcomposition or the formulation may range from about 1.5 to 7, about 2 to7, about 3 to 7, about 4 to 7, or about 5 to 7. In still other aspects,the pH of the composition or formulation may range from about 1.5 to5.5, about 2.5 to 5.5, about 3.5 to 5.5, or about 4.5 to 5.5. Thecomposition or formulation may include a buffering agent to maintain itsacidic pH. In some embodiments, the composition or formulation has a pHvalue between about 4 and 7.

In yet another aspect, the composition or formulation is basic. Incertain aspects, the composition or formulation has a pH of above about7, 8, 9, 10, 11, or 12. In certain other aspects, the pH of thecomposition or formulation may range from about 7 to 12.5, about 7 to11.5, about 7 to 10.5, about 7 to 9.5, or about 7 to 8.5. In still otheraspects, the pH of the composition or formulation may range from about 9to 12.5, about 9 to 11.5, about 9 to 10.5, or about 8.5 to 10. Thecomposition or formulation may include a buffering agent to maintain itsbasic pH. In some embodiments, the composition or formulation has a pHvalue between about 7 and 10.

In still yet another aspect, the composition or formulation is neutral.In certain aspects, the composition or formulation has a pH of about 7.In certain other aspects, the composition or formulation has a pH fromabout 6 to about 8.5, from about 5.5 to 8, about 6 to 8, about 6.5 to8.5, or from about 6.5 to 7.5. The composition or formulation mayinclude a buffering agent to maintain its neutral pH. In someembodiments, the composition or formulation has a pH value between about6 and 8.5.

III. Characteristics

In still yet another embodiment of the present application, thecomposition or formulation is selected from a spray, a gel, a cream, anemulsion, a microemulsion, a lotion, an organogel, an ointment, asolution (e.g., a moderate to highly viscous solution), and atransdermal patch. In a further embodiment, the composition is a gel,for example, a low-viscosity gel, or a spray.

In certain other embodiments, the composition or formulation is designedfor high penetration, for high retention in the skin, or for both highpenetration and high retention. The optimal composition or formulationwill have a balance between penetration and retention, enabling aneffective amount of the active ingredient to pass through the skin, butalso enabling it to stay in the target area for a sufficient duration toalleviate the patient's pain or other symptoms.

In another embodiment, the composition or formulation is designed fortopical efficacy with minimal systemic distribution of the activethrough the body by the circulatory system (e.g., the cardiovascularsystem). The optimal composition or formulation will have low systemicbioavailability, but will effectively treat pain or other symptomsassociated with the site of application.

In an alternative aspect, a composition or formulation comprisingpregabalin has a flux (as determined by the finite dosing Franz cellprocedure of Example 3) about equal to the flux of a known comparativeformulation comprising pregabalin.

In another aspect, the composition or formulation flux is greater thanthe flux of the comparative formulation. In some embodiments, thecomposition or formulation flux is at least 1.5 times the flux of acomparative formulation. In other words, the ratio of (i) the flux ofthe composition or formulation comprising pregabalin to (ii) the flux ofa comparative formulation with pregabalin is greater than 1.0 or atleast about 1.5.

In some embodiments, the composition or formulation comprisingpregabalin has a flux that is at least 2.0 times the flux of acomparative pregabalin formulation. In some embodiments, the compositionor formulation has a flux that is at least 4.0 times the flux of acomparative formulation. In some embodiments, the composition orformulation has a flux that is at least 10.0 times the flux of acomparative formulation.

In another alternative aspect, the present disclosure provides acomposition or formulation comprising pregabalin that provides apregabalin flux (as determined by the Franz cell procedure of Example 3)of at least 0.7 μg hr⁻¹ cm⁻² at 24 hours, at least 1.1 0.7 μg hr⁻¹ cm⁻²at 24 hours, or at least 1.6 0.7 μg hr⁻¹ cm⁻² at 24 hours.

In still another embodiment, the composition or formulation comprisingpregabalin has an enhancement ratio (“ER”) of at least 1.5. In yetanother embodiment, the composition or formulation comprising pregabalinhas an ER of at least 2.0. In still another embodiment, the compositionor formulation comprising pregabalin has an ER that is at least 5.0. Instill another embodiment, the composition or formulation comprisingpregabalin has an ER that is at least 10.0.

In still another embodiment, the composition or formulation comprisingpregabalin provides additional advantages in comparison to previouslydescribed pregabalin compositions. Such advantages may include one ormore of the following: adhering well to the skin, spreading easily,drying more quickly, and showing greater in vivo absorption. In somemore specific embodiments, the drying rate of the formulation is lessthan 20 minutes.

In yet another embodiment, the composition or formulation of the presentapplication is more viscous than water at standard temperature andpressure (“STP”). Alternatively, the composition has a kinematicviscosity of more than about 1 centistokes (“cSt”) or a dynamicviscosity of more than about 1 centipoise (cP). In certain embodiments,the dynamic viscosity of the composition is at most about 2, 3, 4, 5, 7,10, 12, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, 100, 150,200, 250, 500, 1000, 2000, 3000, 5000 or 10,000 cP at STP. In furtherembodiments, the dynamic viscosity is at most about 2, 3, 4, 5, 7, 10,12, 15, 20, 25, 30, 35, 40, 45 or 50 cP at STP. In still furtherembodiments, the dynamic viscosity is at most about 2, 3, 4, 5, 7, 10,12, 15 or 20 cP at STP. In yet other embodiments, the composition isthixotropic (i.e., it decreases in viscosity upon being stirred orshaken). The composition's viscosity can be adjusted by the addition ofa thickening agent, such as a cellulosic thickening agent, for example,hydroxypropyl cellulose, or other thickening agents, or mixturesthereof.

In another embodiment, the composition is acidic. In certainembodiments, the composition has a pH of below about 7.5, of below about6.5, of below about 5.5, of below about 4.5, of below about 3.5, or ofbelow about 2.5. In certain other embodiments, the pH of the compositionranges from about 1.5 to about 7, about 2 to about 7, about 3 to about7, about 4 to about 7, or about 5 to about 7, or is about 6.5.

In another embodiment, the composition is basic. In certain embodiments,the composition has a pH of above about 6.5, of above about 7.0, ofabove about 7.5, of above about 8.5, of above about 9.5, or of aboveabout 10.5. In certain other embodiments, the pH of the compositionranges from about 7 to 11, about 7 to 10, or about 7 to 9, or is about7.5.

In further embodiments, the composition or formulation remains stablefor an acceptable time period between preparation and use when stored ina closed container at normal ambient temperature. In an embodiment, an“acceptable time period” is at least about 30 days, at least about sixmonths, at least about one year, or at least about two years.

In an alternative embodiment, the present disclosure provides acomposition or formulation that degrades by less than 1% over the courseof 6 months at room temperature. In an embodiment, the rate ofdegradation is less than about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2,or less than 0.1%, and all fractions in between, over the course of sixmonths at room temperature.

In an alternative embodiment, the present disclosure provides acomposition or formulation that when applied topically, that is to theskin exterior, facilitates the egress of one or more agents from thebody for analysis or diagnostic purposes.

IV. Specific Compositions

In an embodiment of the present application, there is included apharmaceutical composition comprising, consisting essentially of orconsisting of pregabalin, water, DMSO, propylene glycol, levulinic acid,lauryl lactate, Brij L4, benzyl alcohol and cetylpyridinium chloridemonohydrate (“CPC”). In some embodiments, the present applicationincludes a pharmaceutical composition comprising, consisting essentiallyof or consisting of:

-   -   (a) about 1% w/w to about 5% w/w pregabalin;    -   (b) about 50% w/w to about 70% w/w water;    -   (c) about 10% w/w to about 20% w/w DMSO;    -   (d) about 5% w/w to about 15% w/w propylene glycol;    -   (e) about 1% w/w to about 3% w/w levulinic acid;    -   (f) about 1% w/w to about 3% w/w lauryl lactate;    -   (g) about 1% w/w to about 4% w/w Brij L4;    -   (h) about 1% w/w to about 2% w/w CPC.

In another embodiment of the present application, Brij L4 and CPC areomitted, dimethyl isosorbide is introduced, and water is in partreplaced by ethanol. Accordingly, the present application includes apharmaceutical composition comprising, consisting essentially of orconsisting of:

-   -   (a) about 1% w/w to about 5% w/w pregabalin;    -   (b) about 5% w/w to about 25% w/w water;    -   (c) about 5% w/w to about 25% w/w ethanol;    -   (d) about 10% w/w to about 30% w/w DMSO;    -   (e) about 5% w/w to about 20% w/w propylene glycol;    -   (f) about 5% w/w to about 20% w/w dimethyl isosorbide;    -   (g) about 1% w/w to about 5% w/w levulinic acid;    -   (h) about 1% w/w to about 5% w/w lauryl lactate.

In another embodiment of the present application, propylene glycol isreplaced by diisopropyl adipate and benzyl alcohol is introduced.Accordingly, the present application includes a pharmaceuticalcomposition comprising, consisting essentially of or consisting of:

-   -   (a) about 1% w/w to about 5% w/w pregabalin;    -   (b) about 5% w/w to about 75% w/w water;    -   (c) about 5% w/w to about 25% w/w DMSO;    -   (d) about 5% w/w to about 20% w/w diisopropyl adipate;    -   (e) about 1% w/w to about 5% w/w benzyl alcohol;    -   (f) about 0.5% w/w to about 5% w/w levulinic acid;    -   (g) about 0.5% w/w to about 5% w/w lauryl lactate;    -   (h) about 1% w/w to about 4% w/w Brij L4;    -   (i) about 0.5% w/w to about 2% w/w CPC.

In another embodiment of the present application, benzyl alcohol isintroduced. Accordingly, the present application includes apharmaceutical composition comprising, consisting essentially of orconsisting of:

-   -   (a) about 1% w/w to about 5% w/w pregabalin;    -   (b) about 45% w/w to about 75% w/w water;    -   (c) about 10% w/w to about 25% w/w DMSO;    -   (d) about 5% w/w to about 15% w/w propylene glycol;    -   (e) about 1% w/w to about 5% w/w benzyl alcohol;    -   (f) about 1% w/w to about 3% w/w levulinic acid;    -   (g) about 1% w/w to about 3% w/w lauryl lactate;    -   (h) about 1% w/w to about 4% w/w Brij L4;    -   (i) about 1% w/w to about 2% w/w CPC.

In another embodiment of the present application, benzyl alcohol isintroduced and propylene glycol is replaced in part by dimethylisosorbide. Accordingly, the present application includes apharmaceutical composition comprising, consisting essentially of orconsisting of:

-   -   (a) about 1% w/w to about 3% w/w pregabalin;    -   (b) about 40% w/w to about 75% w/w water;    -   (c) about 10% w/w to about 20% w/w DMSO;    -   (d) about 5% w/w to about 15% w/w propylene glycol;    -   (e) about 5% w/w to about 15% w/w dimethyl isosorbide;    -   (f) about 1% w/w to about 5% w/w benzyl alcohol;    -   (g) about 1% w/w to about 3% w/w levulinic acid;    -   (h) about 1% w/w to about 3% w/w lauryl lactate;    -   (i) about 1% w/w to about 3% w/w Brij L4;    -   (j) about 1% w/w to about 2% w/w CPC.

In some embodiments, the present application includes a pharmaceuticalcomposition comprising, consisting essentially of or consisting of:

-   -   (i) about 1% w/w to about 5% w/w pregabalin;    -   (j) about 50% w/w to about 60% w/w water;    -   (k) about 20% w/w to about 30% w/w DMSO;    -   (l) about 5% w/w to about 10% w/w propylene glycol;    -   (m) about 1% w/w to about 5% w/w benzyl alcohol;    -   (n) about 1% w/w to about 5% w/w levulinic acid;    -   (o) about 1% w/w to about 5% w/w lauryl lactate;    -   (p) about 1% w/w to about 5% w/w Brij L4;    -   (q) about 1% w/w to about 4% w/w CPC.

In another embodiment of the present application, the DMSO concentrationis somewhat reduced, and the water and propylene glycol contents areincreased. Accordingly, the present application includes apharmaceutical composition comprising, consisting essentially of orconsisting of:

-   -   (i) about 1% w/w to about 5% w/w pregabalin;    -   (j) about 55% w/w to about 65% w/w water;    -   (k) about 10% w/w to about 20% w/w DMSO;    -   (l) about 7% w/w to about 15% w/w propylene glycol;    -   (m) about 1% w/w to about 5% w/w benzyl alcohol;    -   (n) about 1% w/w to about 5% w/w levulinic acid;    -   (o) about 1% w/w to about 5% w/w lauryl lactate;    -   (p) about 1% w/w to about 5% w/w Brij L4;    -   (q) about 1% w/w to about 4% w/w CPC.

In another embodiment of the present application, the benzyl alcohol isomitted. Accordingly, the present application includes a pharmaceuticalcomposition comprising, consisting essentially of or consisting of:

-   -   (a) about 1% w/w to about 5% w/w pregabalin;    -   (b) about 55% w/w to about 65% w/w water;    -   (c) about 10% w/w to about 20% w/w DMSO;    -   (d) about 7% w/w to about 15% w/w propylene glycol;    -   (e) about 1% w/w to about 5% w/w levulinic acid;    -   (f) about 1% w/w to about 5% w/w lauryl lactate;    -   (g) about 1% w/w to about 5% w/w Brij L4;    -   (h) about 1% w/w to about 4% w/w CPC.

In another embodiment of the present application, propylene glycol isomitted, and dimethyl isosorbide is introduced. Accordingly, the presentapplication includes a pharmaceutical composition comprising, consistingessentially of or consisting of:

-   -   (a) about 1% w/w to about 5% w/w pregabalin;    -   (b) about 55% w/w to about 65% w/w water;    -   (c) about 10% w/w to about 20% w/w DMSO;    -   (d) about 7% w/w to about 15% w/w dimethyl isosorbide;    -   (e) about 1% w/w to about 5% w/w benzyl alcohol;    -   (f) about 1% w/w to about 5% w/w levulinic acid;    -   (g) about 1% w/w to about 5% w/w lauryl lactate;    -   (h) about 1% w/w to about 5% w/w Brij L4;    -   (i) about 1% w/w to about 4% w/w CPC.

In another embodiment of the present application, propylene glycol isomitted, and diisopropyl adipate is introduced. Accordingly, the presentapplication includes a pharmaceutical composition comprising, consistingessentially of or consisting of:

-   -   (a) about 1% w/w to about 5% w/w pregabalin;    -   (b) about 55% w/w to about 65% w/w water;    -   (c) about 10% w/w to about 20% w/w DMSO;    -   (d) about 7% w/w to about 15% w/w diisopropyl adipate;    -   (e) about 1% w/w to about 5% w/w benzyl alcohol;    -   (f) about 1% w/w to about 5% w/w levulinic acid;    -   (g) about 1% w/w to about 5% w/w lauryl lactate;    -   (h) about 1% w/w to about 5% w/w Brij L4;    -   (i) about 1% w/w to about 4% w/w CPC.

In another embodiment of the present application, DMSO is replaced inpart by transcutol (2-(2-ethoxyethoxy)ethanol). Accordingly, the presentapplication includes a pharmaceutical composition comprising, consistingessentially of or consisting of:

-   -   (a) about 1% w/w to about 5% w/w pregabalin;    -   (b) about 50% w/w to about 60% w/w water;    -   (c) about 10% w/w to about 20% w/w DMSO;    -   (d) about 5% w/w to about 10% w/w propylene glycol;    -   (e) about 1% w/w to about 5% w/w benzyl alcohol;    -   (f) about 1% w/w to about 5% w/w levulinic acid;    -   (g) about 1% w/w to about 5% w/w lauryl lactate;    -   (h) about 1% w/w to about 5% w/w Brij L4;    -   (i) about 1% w/w to about 4% w/w CPC    -   (j) about 7% w/w to about 15% w/w transcutol.

In a further embodiment of the present application, there is included apharmaceutical composition comprising, consisting essentially of orconsisting of pregabalin, water, DMSO, and CPC. Accordingly, the presentapplication includes a pharmaceutical composition comprising, consistingessentially of or consisting of:

-   -   (a) about 1% w/w to about 5% w/w pregabalin;    -   (b) about 60% w/w to about 80% w/w water;    -   (c) about 10% w/w to about 30% w/w DMSO;    -   (d) about 1% w/w to about 5% w/w levulinic acid;    -   (e) about 1% w/w to about 4% w/w CPC.

In a further embodiment of the present application, lauryl lactate isalso introduced. Accordingly, the present application includes apharmaceutical composition comprising, consisting essentially of orconsisting of:

-   -   (a) about 1% w/w to about 5% w/w pregabalin;    -   (b) about 60% w/w to about 80% w/w water;    -   (c) about 10% w/w to about 30% w/w DMSO;    -   (d) about 1% w/w to about 5% w/w levulinic acid;    -   (e) about 1% w/w to about 4% w/w CPC    -   (f) about 1% w/w to about 4% w/w lauryl lactate.

In a further embodiment of the present application, Brij L4 is alsointroduced. Accordingly, the present application includes apharmaceutical composition comprising, consisting essentially of orconsisting of:

-   -   (a) about 1% w/w to about 5% w/w pregabalin;    -   (b) about 60% w/w to about 80% w/w water;    -   (c) about 10% w/w to about 30% w/w DMSO;    -   (d) about 1% w/w to about 5% w/w levulinic acid;    -   (e) about 1% w/w to about 4% w/w CPC    -   (f) about 1% w/w to about 4% w/w oleyl alcohol    -   (g) about 2% w/w to about 5% w/w Brij L4.

In a further embodiment of the present application, oleyl alcohol isintroduced in place of lauryl lactate. Accordingly, the presentapplication includes a pharmaceutical composition comprising, consistingessentially of or consisting of:

-   -   (a) about 1% w/w to about 5% w/w pregabalin;    -   (b) about 60% w/w to about 80% w/w water;    -   (c) about 10% w/w to about 30% w/w DMSO;    -   (d) about 1% w/w to about 5% w/w levulinic acid;    -   (e) about 1% w/w to about 4% w/w CPC    -   (f) about 1% w/w to about 4% w/w oleyl alcohol.

In a further embodiment of the present application, Brij L4 is alsointroduced is also introduced. Accordingly, the present applicationincludes a pharmaceutical composition comprising, consisting essentiallyof or consisting of:

-   -   (a) about 1% w/w to about 5% w/w pregabalin;    -   (b) about 60% w/w to about 80% w/w water;    -   (c) about 10% w/w to about 30% w/w DMSO;    -   (d) about 1% w/w to about 5% w/w levulinic acid;    -   (e) about 1% w/w to about 4% w/w CPC    -   (f) about 1% w/w to about 4% w/w oleyl alcohol    -   (g) about 2% w/w to about 5% w/w Brij L4.

In a further embodiment of the present application all compositionsadditionally comprise a thickening agent, in an amount of about 0.5% w/wto about 5.0% w/w, about 0.5% w/w to about 3.0% w/w, about 0.5% w/w toabout 2.0% w/w, or about 1.5% w/w to about 2.5% w/w.

In a further embodiment of the present application all compositionsadditionally comprise at least one preservative, for example CPC, ormethyl paraben and/or propyl paraben, in an amount of about 0.1% w/w toabout 5.0% w/w, about 0.1% w/w to about 3.0% w/w or about 0.1% w/w toabout 1.0% w/w.

V. Methods of Preparation

In some embodiments, the pharmaceutical compositions are formulated as aspray, cream, an emulsion, a microemulsion, a gel (e.g., a hydrogel, anorganogel, an inorganic or silica gel, a high-viscosity gel or alow-viscosity gel), a lotion, a lacquer, an ointment, a solution (e.g.,a moderate to highly viscous solution), or a transdermal patch. In asuitable embodiment, the composition is a gel, for example, alow-viscosity gel or a spray. Alternatively, the composition is ahigh-viscosity gel. The pharmaceutical composition of the presentapplication may also be formulated as a transdermal patch. Low viscositygels are, for example, gels having a dynamic viscosity in the range ofabout 400-4000 cP at STP. High viscosity gels are, for example, gelshaving a dynamic viscosity of at least 4000 cP at STP.

Methods of preparing compositions for topical administration are knownin the art (see, for example, Remington's Pharmaceutical Sciences,2000-20th edition, and The United States Pharmacopeia: The NationalFormulary, USP 24 NF19, published in 1999). In the present applicationcompositions include those based on an aqueous or hydroalcoholicchassis. Therefore water soluble components are dissolved in the waterphase and components soluble in the organic or alcohol phase aredissolved in the organic and/or alcohol phase and the two solutions,once homogeneous, are slowly combined and mixed to homogeneity withgentle heating and stirring, mixing or vortexing as needed. In anotherembodiment, all ingredients are combined directly and mixed tohomogeneity with gentle heating and stirring, mixing or vortexing asneeded.

VI. Methods of Treatment

Neuropathic pain, that is, pain caused by a lesion or disease of thesomatosensory nervous system, presents a significant burden toindividuals and to society by increasing disability and reducingproductivity and quality of life, with concomitant increases inhealthcare resource utilization and costs. Neuropathic pain, which maybe either peripheral or central depending upon the site of the lesionwithin the nervous system, is characterized by a delayed onset of painafter nervous system lesion, pain in an area of sensory loss,spontaneous ongoing or paroxysmal pain, and evoked types of pain such ashyperalgesia or allodynia.

Estimates of the United States (“US”) prevalence of neuropathic pain are6-7%, corresponding to roughly 20M afflicted, although the estimatevaries widely depending on the tools used to identify neuropathic painand the estimate, as a result, likely reflects a lower bound. The mostprevalent forms of neuropathic pain are diabetic peripheral neuropathy(“DPN”), cervical radiculopathy, carpal tunnel syndrome, and postherpetic neuralgia (“PHN”). Diabetes mellitus afflicts more than 25Mpersons in the US, of which an estimated 15% experience DPN, althoughother sources provide a still higher estimate. The lifetime risk ofherpes zoster (“HZ”), also known as shingles, is upwards of 25% in thegeneral population; nearly 1 million new HZ cases occur annually in theUnited States. Some 7-27% of HZ patients will experience PHN.

Peripheral neuropathic pain conditions are treated with a tricyclicantidepressant (“TCA”); duloxetine, a selective dual reuptake inhibitorof both serotonin and noradrenaline (“SNRI”); the anticonvulsantspregabalin and gabapentin; and a topical lidocaine patch. Otherapproaches to treat peripheral neuropathic pain conditions include useof opiates such as the synthetic opioid tramadol, morphine and oxycodonecontrolled release; membrane stabilizers; the antioxidant α-lipoic acid;topical capsaicin; certain antidepressant and antiepileptic medications;mexiletine; and N-methyl-d-aspartate (“NMDA”) receptor antagonists.Percutaneous electrical nerve stimulation (“PENS”) or transcutaneouselectrical nerve stimulation (“TENS”) have been used, and in extremecases of DPN unresponsive to pharmacotherapy, occasional use ofelectrical spinal cord stimulation might be indicated.

Despite this slate of treatment options, peripheral neuropathic pain isoften poorly managed and new, more effective and more convenienttreatments are sorely needed.

Some embodiments provide for a method for treating a subject sufferingfrom pain, said method comprising the topical administration to saidsubject of a therapeutically effective amount of a formulation asdescribed herein.

In certain embodiments, the disclosure describes a method for treatingpain in a subject comprising the step of applying a topical formulationto a subject to prevent or ameliorate pain, such as peripheralneuropathic pain.

In certain aspects, the pharmaceutical composition is applied to a limbor torso or other suitable body area of the subject. In someembodiments, the pharmaceutical composition is applied to the skincovering the tissue or tissues affected.

In other aspects, the subject is a human. Alternatively, the subject isa non-human mammal.

In still other aspects, the active agent alleviates pain. In someembodiments, the pain may be neuropathic pain. In some embodiments, thepain is DPN, cervical radiculopathy, carpal tunnel syndrome or PHN.

In yet still other aspects, the treatment is continued for at least oneweek, for one month, or for 12 weeks. In some embodiments, the treatmentis continued for at least six months.

In one embodiment, the treatment may be administered once a day. Inanother embodiment, the treatment may be administered twice a day. Instill another embodiment, the treatment may be administered three timesa day. In yet another embodiment, the treatment may be administered fourtimes a day. In some embodiments, the treatment is administered one totwo times a day.

Formulation embodiments of the present disclosure are useful andeffective when applied topically to treat a condition. The amount of theactive agent present in the composition will be the amount that istherapeutically effective, i.e., an amount that will result in theeffective treatment of the condition (e.g., DPN or PHN) when applied.The therapeutically effective amount will vary depending on the subjectand the severity of the affliction and can be determined routinely byone of ordinary skill in the art.

In another aspect, the formulation comprising an active agent providesabout equal flux (as determined by the Franz cell procedure of Example3) as a comparative formulation containing the same active agent.

In another aspect, the formulation comprising an active agent providesbetter flux than a comparative formulation containing the same activeagent. In some embodiments, the flux of the formulation is at least 1.5times the flux of the comparative formulation's active. In other words,the ratio of (i) the formulation's active agent flux to (ii) thecomparative formulation's active agent is greater than 1.0 or at leastabout 1.5. In some embodiments, the formulation has a flux that is atleast 2.0 times greater than the flux of the comparative formulation. Insome embodiments, the formulation has a flux that is at least 4.0 timesgreater than the comparative formulation's flux. In some embodiments,the formulation has a flux that is at least 10.0 times greater than thecomparative formulation's flux.

In an alternative aspect, a formulation comprising pregabalin has a fluxabout equal to the flux of a known comparative formulation comprisingpregabalin.

In another aspect, the composition flux is greater than the flux of thecomparative formulation. In some embodiments, the composition flux is atleast 1.5 times the flux of a comparative formulation. In other words,the ratio of (i) the flux of the composition comprising pregabalin to(ii) the flux of a comparative formulation with pregabalin is greaterthan 1.0 or at least about 1.5.

In some embodiments, the composition comprising pregabalin has a fluxthat is at least 2.0 times the flux of a comparative pregabalinformulation. In some embodiments, the composition has a flux that is atleast 4.0 times the flux of a comparative formulation. In someembodiments, the composition has a flux that is at least 10.0 times theflux of a comparative formulation.

In another alternative aspect, the present disclosure provides acomposition comprising pregabalin provides a pregabalin flux (asdetermined by the Franz cell procedure of Example 3) of at least 0.7 μghr⁻¹ cm⁻² at 24 hours, at least 1.1 μg hr⁻¹ cm⁻² at 24 hours, or atleast 1.6 μg hr⁻¹ cm⁻² at 24 hours.

The compositions of the disclosure are suitable for use on mammalianskin.

VII. Dispensing System

Compositions of the present disclosure may, if desired, be presented ina pouch, bottle, pump bottle, spray bottle, foaming dispenser or otherclosure system approved by the US Food and Drug Administration (“FDA”)or other regulatory body, which may contain one or more unit dosageforms containing the active ingredient. The bottle or dispenser may alsobe accompanied by a notice associated with the container in a formprescribed by a governmental agency regulating the manufacture, use, orsale of pharmaceuticals, the notice indicating approval by the agency.

In some aspects, the compositions of the present disclosure may beformulated into products that can be dispensed from a reservoir using arelease assembly (e.g., a hand pump) to dispense an amount of thecomposition whenever the release assembly is put into action. The amountof the composition dispensed by the pump may or may not be metered todispense a consistent amount of formulation.

EXAMPLES Example 1: General Procedure for Formulation Preparation

A desired weight of an active agent, such as pregabalin, is weighed in aglass media bottle. DMSO, water and the alcohols are introduced. Themedia bottle is capped and the contents sonicated at room temperatureuntil the active agent is fully dissolved. The remaining excipients arethen added and the resulting mixture are then briefly mixed until aclear, homogeneous solution is obtained.

Example 2: Exemplary Formulations

Formulations of compositions as provided in Tables 1-6 (amounts shown as% w/w) were prepared using the general procedure described under Example1.

TABLE 1 Exemplary pregabalin formulation compositions TrPg108-2 TrPg200TrPg107-2 TrPg201 TrPg101-2 TrPg202 TrPg204 TrPg205 TrPg206 Pregabalin2.50 2.50 2.50 2.50 2.45 2.50 2.49 2.49 2.49 Ethanol 24.51 20.00 9.9519.90 19.90 Water 95.50 95.50 93.50 93.50 69.12 45.00 59.70 24.88 19.90Cetylpyridinium 2.00 2.00 2.00 2.00 1.96 chloride monohydrate Levulinicacid 2.00 2.00 1.96 2.99 DMSO 14.50 14.93 29.85 19.90 Dimethyl 4.98 4.9814.93 isosorbide Propylene glycol 7.50 4.98 9.95 16.92 Glycerin 2.50Lauryl lactate 3.98 2.99 Benzyl alcohol 2.00 Brij S20 3.00 Brij L4 (30)3.00 2.99 3.98

TABLE 2 Exemplary pregabalin formulation compositions TrPg207 TrPg208TrPg209 TrPg210 TrPg218 TrPg219 Pregabalin 1.95 1.75 1.71 1.68 1.70 1.48Ethanol Water 73.05 65.38 64.04 62.75 63.61 55.33 Cetylpyridinium 1.561.40 1.37 1.34 1.36 1.18 chloride monohydrate Levulinic acid 1.56 1.401.37 1.34 1.18 DMSO 19.53 17.48 17.12 16.78 17.01 26.63 Propylene glycol10.49 10.27 10.07 10.20 8.88 Lauryl lactate 2.05 2.01 2.04 1.78 Benzylalcohol 2.01 2.04 1.78 Brij L4 (30) 2.34 2.10 2.05 2.01 2.04 1.78

TABLE 3 Exemplary pregabalin formulation compositions TrPg209 TrPg210TrPg211 TrPg212 TrPg220 Pregabalin 1.71 1.68 1.68 1.68 1.48 Water 64.0462.75 62.75 62.75 55.33 Cetylpyridinium 1.37 1.34 1.34 1.34 1.18chloride monohydrate Levulinic acid 1.37 1.34 1.34 1.34 1.18 DMSO 17.1216.78 16.78 16.78 14.79 Dimethyl 10.07 isosorbide Propylene 10.27 10.078.88 glycol Diisopropyl 10.07 adipate Lauryl lactate 2.05 2.01 2.01 2.011.78 Transcutol 11.83 Benzyl alcohol 2.01 2.01 2.01 1.78 Brij L4 (30)2.05 2.01 2.01 2.01 1.78

TABLE 4 Exemplary pregabalin formulation compositions TrPg202 TrPg204TrPg206 TrPg217 TrPg219 Pregabalin 2.50 2.49 2.49 1.68 1.48 Ethanol20.00 9.95 19.90 Water 45.00 59.70 19.90 62.75 55.33 Cetylpyridinium1.34 1.18 chloride monohydrate Levulinic acid 2.99 1.34 1.18 DMSO 14.5014.93 19.90 16.78 26.63 Dimethyl 4.98 14.93 isosorbide Propylene 7.504.98 16.92 10.07 8.88 glycol Glycerin 2.50 Lauryl lactate 2.99 2.01 1.78Benzyl alcohol 2.00 2.01 1.78 Brij S20 3.00 2.01 Brij L4 (30) 3.00 2.991.78

TABLE 5 Exemplary pregabalin formulation compositions TrPg210 TrPg213TrPg215 Pregabalin 1.68 1.66 1.71 Water 62.75 62.13 64.04Cetylpyridinium 1.34 1.33 chloride monohydrate Levulinic acid 1.34 1.33DMSO 16.78 16.61 17.12 Propylene 10.07 9.97 10.27 Glycol Lauryl lactate2.01 1.99 2.05 Benzyl Alcohol 2.01 1.99 2.05 Brij L4 (30) 2.01 1.99 2.05HY117 1.00 Carbopol 971 0.68

TABLE 6 Exemplary pregabalin formulation compositions TrPg300 TrPg301TrPg302 TrPg303 TrPg304 TrPg305 TrPg306 TrPg307 TrPg308 Pregabalin 2.602.55 2.50 2.00 1.94 1.95 1.95 1.92 1.89 Water 97.40 95.41 93.50 74.8072.48 73.05 73.05 71.92 70.83 Cetylpyridinium 2.04 2.00 1.60 1.55 1.561.56 1.54 1.52 chloride monohydrate Levulinic acid 2.00 1.60 1.55 1.561.56 1.52 DMSO 20.00 19.38 19.53 19.53 19.23 18.94 Lauryl lactate 2.34Brij L4 (30) 3.10 3.08 3.03 Oleyl Alcohol 2.34 2.31 2.27

Example 3: Skin Permeation Measurement

Franz diffusion cell experiments were used to analyze flux rates ofpregabalin from compositions taught under the present disclosure acrossa substrate membrane. Franz diffusion cells are a common and well knownmethod for measuring transdermal flux rates. The general Franz cellprocedure is described by Franz (J. Invest. Dermatol., 1975, 64,190-195).

In the present examples, Franz diffusion cells (“FDC”s) with a 3.3 mLreceptor well volume were used with split thickness human cadaver skin(0.015″-0.018″, AlloSource or New York Firefighters Tissue Bank). Thedonor well had an area of about 0.55 cm². The receptor wells were filledwith isotonic phosphate-buffered saline solution (“PBS”) doped with0.01% sodium azide. The receptor wells of the FDCs were maintained at37° C. (the temperature on the surface of the skin is 32° C.) in astirring dry block with continual agitation via a stir bar. The flangesof the Franz cells were coated with vacuum grease to ensure a completeseal and donor and receptor chambers were clamped about the skin pieceunder uniform pressure using a pinch clamp (SS #18 VWR 80073-350).

After the FDCs were assembled, the skin was allowed to hydrate for 20minutes in contact with the receptor fluid. Any FDCs that evidenced anyleakage during this period were discarded. The integrity and quality ofeach skin piece was tested prior to application of the test formulationsthrough measurement of the transdermal flux of tritiated water. Skinpieces evidencing an excessively high tritiated water flux werediscarded and the tritiated water fluxes of accepted skin pieces wereused to guide the distribution of test formulation samples over the skinpiece set. After removal of the tritiated water samples from the donorwells, the clamps and donor wells were removed. The skin was tapped drywith a KimWipe and the receptor well solutions were replenished withfresh receptor well medium. The donor wells and clamps were thenre-applied.

Six replicates of each of the test formulations are examined, typicallyin a batch of some 36 FDCs in total. Each test formulation was appliedat a finite dose of 5 μL (9 mg cm⁻²) on skin maintained at 32° C.throughout the experiments. The Receptor Fluid was stirred with amagnetic stir bar throughout. A sample was abstracted from each receptorwell at preset times, typically 4 h and 22 h or 24 h, the receptorwell-being replenished with fresh receptor fluid. The concentration ofpregabalin in each receptor well sample was assayed by a verifiedhigh-performance liquid chromatography (“HPLC”) orliquid-chromatography-mass spectrometry (“LC-MS”) analytical method.

At the end of the experiment (22 h or 24 h), residual formulation wasremoved from the skin exterior with a pipette. The FDC was disassembledand the skin washed twice with EtOH-Water 50-50 and wiped dry with aKimWipe. The successive topmost layers of the stratum corneum areremoved by three (3) times applying cellophane tape to the skin and thenpulling off the tape. Tape strippings were discarded, the materialpresent in those peripheral layers being considered absorbed onlysuperficially. The epidermal and dermal layers were separated, usingmild heating if required. The epidermal and dermal sections were placedinto 4 ml glass vials. 2 ml of extraction solvent was added to each vialand the vials allowed to incubate for 24 h. At the end of the extractionperiod, aliquots of the extraction solvent were drawn, filtered andanalyzed. Measurements were made in six-fold replicates. Theconcentration of pregabalin in the samples was analyzed the verifiedHPLC or LC-MS method.

Measurements of the permeation of pregabalin through and retention ofpregabalin in the epidermal and dermal compartments of human cadaverskin were made according to the above procedure. The results areprovided in FIGS. 1 to 10D. Numbered formulations “PreG” of FIGS. 1-4correspond to formulations “TrPg” of Tables 1-5 above. Additionally,FIG. 5A to 5C summarizes the data from formulations of Table 1, FIG. 6Ato 6C summarizes the data from formulations of Table 2, FIG. 7A to 7Csummarizes the data from formulations of Table 3, FIG. 8A to 8Csummarizes the data from formulations of Table 4, FIG. 9A to 9Csummarizes the data from formulations of Table 5, and FIG. 10A to 10Dsummarizes the data from formulations of Table 6.

Comparing results for TrPg210 (for which results from three independentskin permeation studies (the average of which is plotted in FIG. 7A to7C) provide average enhancement ration of 2.1 (3); 8.1 (7); 1.3 (1) foreach of 4 h, 24 h and epidermis respectively), with those for TrPg 217(for which the corresponding numbers are 1.1 (4); 3.1 (8); 1.4 (3)). Itis contemplated that the smaller polyethylene glycol alkyl ether, BrijL4 (polyethylene glycol dodecyl ether also termed polyoxyethylene (4)lauryl ether; (C₂H₄O)_(n)C₁₂H₂₆O; n_(average)=4, average molecularweight 362) contributes substantially more to increased pregabalin fluxthan the larger Brij S20 (polyoxyethylene monooctadecyl ether, alsotermed polyoxyethylene (20) stearyl ether, formerly termed Brij™ 78;C₁₈H₃₇(OCH₂CH₂)_(n)OH, n-20, average molecular weight 1,152).

It is understood that the examples and embodiments described herein arefor illustrative purposes only. Various modifications or changes inlight thereof will be suggested to persons skilled in the art and are tobe included within the spirit and purview of this application and thescope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

1.-24. (canceled)
 25. A topical formulation comprising: (i) at least oneactive agent, (ii) water, (iii) dimethyl sulfoxide (“DMSO”), (iv) a ketoacid and (v) an ester of a fatty alcohol and an α-hydroxy acid and/or ofa fatty acid and an alcohol.
 26. The topical formulation of claim 25,wherein said keto acid is levulinic acid.
 27. The topical formulation ofclaim 25, wherein said ester of a fatty alcohol and an α-hydroxy acid islauryl lactate.
 28. The topical formulation of claim 25, wherein saidester of a fatty acid and an alcohol is isopropyl myristate.
 29. Thetopical formulation of claim 25, further comprising a polyalkyleneglycol alkyl ether.
 30. The topical formulation of claim 25, furthercomprising cetylpyridinium chloride.
 31. The topical formulation ofclaim 29, wherein said polyalkylene glycol alkyl ether is a polyethyleneglycol alkyl ether.
 32. The topical formulation of claim 25, furthercomprising a monohydric alcohol. 33.-43. (canceled)
 44. A topicalformulation comprising: (i) at least one active agent, (ii) water, (iii)about 10% to about 20% w/w dimethyl sulfoxide (“DMSO”), (iv) about 0.5%to about 5% w/w of a keto acid, and (v) about 0.5% to about 5% of anester of a fatty alcohol and an α-hydroxy acid and/or of a fatty acidand an alcohol, (vi) about 5% to about 15% propylene glycol, and (vii)about 1% to about 4% polyalkylene glycol alkyl ether.
 45. The topicalformulation of claim 44, wherein the keto acid is levulinic acid. 46.The topical formulation of claim 44, wherein the ester of a fattyalcohol and an α-hydroxy acid is lauryl lactate.
 47. The topicalformulation of claim 44, wherein the polyalkylene glycol alkyl ether ispolyethylene glycol dodecyl ether.
 48. The topical formulation of claim44, further comprising cetylpyridinium chloride.
 49. The topicalformulation of claim 44, further comprising dimethyl isosorbide.
 50. Thetopical formulation of claim 44, further comprising a monohydricalcohol.
 51. The topical formulation of claim 44, comprising about 50%to about 70% water.
 52. The topical formulation of claim 45, comprisingabout 1% to about 3% w/w levulinic acid.
 53. The topical formulation ofclaim 46, comprising about 1% to about 3% lauryl lactate.
 54. Thetopical formulation of claim 44, comprising about 12% to about 20% w/wDMSO.
 55. The topical formulation of claim 48, comprising about 1% toabout 2% cetylpyridinium chloride.